DESCRIPTION (Verbatim from Applicant's Abstract): The overall goal of this research is to develop a non-invasive and quantitative method to monitor progression of NP-C disease and its response to successful therapy. Niemann-Pick type C disease (NP-C) is an inheritable defect in intracellular cholesterol trafficking with a gene frequency of 1:200. Although it is rare, the defect is particularly devastating because most NP-C suffers present in early childhood with progressive ataxia, leading to death before puberty. The major gene responsible for NP-C was identified in 1997, and its structure lends some clues as to its cellular biochemical function. Investigating the molecular mechanisms underlying this disease is leading to development of rational therapies. Development of therapies is also being helped with a NP-C mouse model. A major problem is that current therapeutic endpoints are limited to qualitative measures of neurological response patterns or delayed onset of death. These endpoints are far from ideal since they are neither sensitive nor quantitative. A sensitive, reliable and quantitative method to monitor progression of NP-C and regression in response to successful therapy is needed. Magnetic Resonance Imaging (MRI) has great potential to provide such a method because it is non-invasive, it is equally applicable to animal models and to human patients, and it can generate data which are quantifiably sensitive to changes in NP-C. Since MRI analyses are non-invasive, therapeutic responses can be benchmarked against the subjects' own background, and this increases the sensitivity of measurement several fold. Because MRI methods are applicable to animal models and human patients, methods developed for monitoring NP-C in mice can be translated rapidly to the human patient population. The goal of this research is to develop MRI methods to monitor NP-C that are sensitive, reliable and quantitative. Such methods will hasten the development and application of rational therapies and improve treatment of human patients. The approach to this goal will involve quantitatively relating the MR-visible parameters to the progression of the disease, defined using neurological, biochemical and histological markers. MR techniques to be investigated are magnetization transfer contrast (MTC) imaging and diffusion imaging (DI). Preliminary data indicate that these modalities can successfully discriminate NP-C mice from normal littermates. The two major organ systems to be investigated are the brain and liver, since these are greatly affected in clinical disease. These methods will then be used to monitor the progression of NP-C disease in individual homozygous NP-C mice and those undergoing experimental therapies. A direct outcome of this project will be the development of quantitative and reliable methods, which can be exported to other labs for animal work, or to clinical centers for analyses of human patients. We will continue to work with other NP-C researchers to either analyze their animals undergoing therapy or to help them apply these methods at their institutions.